K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration


Phasic activation of the dopamine (DA) midbrain system in response to unexpected reward or novelty is critical for adaptive behavioral strategies. This activation of DA midbrain neurons occurs via a synaptically triggered switch from low-frequency background spiking to transient high-frequency burst firing. We found that, in medial DA neurons of the substantia nigra (SN), activity of ATP-sensitive potassium (K-ATP) channels enabled NMDA-mediated bursting in vitro as well as spontaneous in vivo burst firing in anesthetized mice. Cell-selective silencing of K-ATP channel activity in medial SN DA neurons revealed that their K-ATP channel–gated burst firing was crucial for novelty-dependent exploratory behavior. We also detected a transcriptional upregulation of K-ATP channel and NMDA receptor subunits, as well as high in vivo burst firing, in surviving SN DA neurons from Parkinson's disease patients, suggesting that burst-gating K-ATP channel function in DA neurons affects phenotypes in both disease and health.

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Figure 1: In vivo firing characteristics and differences of burst properties of identified DA neurons in the SN and VTA.
Figure 2: K-ATP channels selectively control in vivo burst firing in m-SN DA neurons.
Figure 3: Co-activation of K-ATP channels and NMDA receptors is sufficient to induce bursting in vitro.
Figure 4: K-ATP channel activation shifts maximal firing frequencies induced by current injection into the burst range in m-SN DA neurons in vitro.
Figure 5: Virus-mediated expression of dominant-negative Kir6.2 pore mutant induced selective functional silencing of K-ATP channels in SN DA neurons.
Figure 6: Cell-selective silencing of K-ATP channels in SN DA neurons using virally mediated gene transfer is sufficient to prevent burst firing in m-SN neurons.
Figure 7: K-ATP channels in m-SN DA neurons are necessary for novelty-dependent exploratory behavior.
Figure 8: Increased mRNA levels of the K-ATP channel subunit SUR1 and high burst firing in SN DA neurons from Parkinson's disease patients.


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We thank S. Petzoldt, H. Schalk and A. Parg for assistance in immunohistochemistry, and M. Fauler for mRNA expression data analysis. The study was supported by Gemeinnützige Hertiestiftung (J.R. and B.L.), SFB815 (J.R.), SFB497 (B.L.), BMBF Nationales Genomforschungsnetzwerk NGFN-II/plus (01GS08134, J.R. and B.L.), Alfried Krupp prize (B.L.), LOEWE-Schwerpunkt Neuronale Koordination Forschungsschwerpunkt Frankfurt NeFF (J.R. and G.S.), Bernstein Fokus Neurotechnology Frankfurt (G.S. and M.B.), doctoral fellowship Studienstiftung des deutschen Volkes (J.S.) and Medical Research Council UK (U138197109, P.J.M.).

Author information

J.S. carried out in vivo electrophysiology, juxtacellular labeling (training by P.J.M.), viral gene transfer, retrograde tracing, immunocytochemistry, microscopy and data analyses. V.K. and J.S. carried out animal behavior experiments. J.R. performed in vitro electrophysiology. The GLO model was designed by M.B. and G.S. F.S. and B.L. carried out laser microdissection and molecular biology. S.S. generated Kir6.2−/−. K.A.Z. performed human SN recordings. J.S., P.J.M., B.L. and J.R. designed the study and wrote the manuscript.

Correspondence to Birgit Liss or Jochen Roeper.

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Schiemann, J., Schlaudraff, F., Klose, V. et al. K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat Neurosci 15, 1272–1280 (2012). https://doi.org/10.1038/nn.3185

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